AND ABSTRACT Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract that affect up to 3 million Americans. IBD is thought to be driven by inappropriate immune responses to an altered gut microbiome, or dysbiosis, with a disease course characterized by remitting and relapsing episodes of inflammation, or flares. Despite increasing knowledge regarding the relationship between the gut microbiome, dysbiosis, and the impact on mucosal immunity, much remains unknown regarding the inciting environmental factors and underlying mechanisms that result in intestinal inflammation. In addition, although there have been dramatic improvements in IBD therapeutics, the disease course has remained relatively unchanged with patients remaining at high risk for recurrent flares, complications, surgeries, and reduced quality of life. Enteric infections are a common cause of dysbiosis, and have been implicated as an environmental factor in onset and flare of IBD. Our preliminary data has identified enteric infection in nearly 30% of IBD flares, with the most common pathogens including Clostridioides difficile, Enteropathogenic Escherichia coli (EPEC), and norovirus. This K23 proposal will address this knowledge gap by testing the hypothesis that enteric infection is a major environmental factor in flare of IBD, producing a specific subtype of flare characterized by a unique clinical presentation and impact on IBD progression, distinct from patients with a flare but without an enteric infection. To test this hypothesis, we will recruit and prospectively follow patients with flare of IBD with the presence of C. difficile, EPEC, or norovirus, and separately with flare of IBD but without a gastrointestinal pathogen. We will identify the clinical (Aim 1), gut microbiome, and immune factors (Aim 2) that distinguish flares complicated by enteric infection to directly improve IBD outcomes in these patients. This will be the first study to longitudinally determine the clinical and molecular impact of specific enteric pathogens on the course of IBD with the potential to reveal innovative mechanisms regarding the role of enteric pathogens as environmental factors in IBD, and novel approaches to the management of this complex clinical scenario. To conduct this research, further training is required, and Dr. Axelrad has assembled a multidisciplinary team of mentors to provide detailed training in immunology and microbiology, biostatistics and quantitative methods, and funding and grantsmanship. This K23 proposal will position Dr. Axelrad to accomplish the goal of determining the role of specific enteric pathogens in flares of IBD and facilitate his development into an independent, patient-oriented and translational investigator in the field of IBD.
Enteric infections are a common cause of dysbiosis, and have been implicated as an environmental factor in onset and flare of IBD. Our preliminary data has identified enteric infection in nearly 30% of IBD flares, with the most common pathogens including Clostridioides difficile, Escherichia coli, and norovirus. This study will determine the clinical and molecular impact of specific enteric pathogens on the course of IBD to directly improve IBD outcomes and further elucidate mechanisms of pathogen-associated dysbiosis underlying chronic gastrointestinal inflammation.
